The objective of this proposal is to extend our studies on the theoretical underpinning of clinical genetics. The properties and the applications of two-locus models will be combined with special emphasis on congenital heart disease. Age-dependent phenotypes and their implications for genetic counseling will be applied with particular application to heritable polyposis of the colon. Statistical aspects of age-dependent separation of indefinite phenotypes will be applied to blood lipid levels and blood pressure. The theoretical statistical properties of evolutionary fitness will be further explored and the robustness and efficiency of Sigler's method when applied to finite samples from the truncated negatice binomial distribution will be examined. A unified theory of ascertainment bias will be completed, to accommodate not only the classical patterns but more general forms (e.g. erythroblastosis fetalis and other age- and order-dependent disorders).